Human Epilepsy Genetics - Mosaic Mutations in Focal Epilepsy

Project Summary: Epilepsy is a debilitating disease affecting 1 in 26 people (3-4% lifetime risk), making it the third most common neurological disorder in the United States. Antiepileptic drugs (AEDs) remain the mainstay of epilepsy therapy, but the long-term sequelae of uncontrolled epilepsy, including underachievement, social isolation, and heightened rates of depression and sudden death, bring into consideration more aggressive strategies for patients whose disease is recalcitrant to pharmacotherapy. The most prevalent form of intractable, non-lesional focal epilepsy in adults is mesial temporal lobe epilepsy (mTLE), and the causal mechanisms of mTLE remain poorly understood. mTLE often starts in adolescence or early adulthood, often following a history of earlier febrile seizures or head trauma, and often becoming more intractable with time. Sclerotic changes of the hippocampus (HS) often appear radiographically. With proper localization, mTLE is amenable to surgical intervention, resulting in seizure freedom or improvement in up to two thirds of cases. Our preliminary data, based on the genomic study of these resected tissues samples, implicate somatic activating variants in multiple RAS pathway genes in mTLE. The major goals of this study are to: sequence larger numbers of mTLE samples resected for epilepsy control, in order to confirm and extend our preliminary findings on the role of RAS activation in mTLE, and to identify other potential genetic regulators of mTLE; delineate the transcriptional effects of somatic mutation on specific cell types within the epileptic tissue ; and to identify the exact cell type(s) that carry mosaic variants, and the transcriptional effects on those variant- positive cells, compared to surrounding variant-negative cells in mTLE. Our prior experience in the development, use, and analysis of single cell genomic data, together with our promising preliminary data on mTLE and the availability of high-quality samples in-hand, indicate a high likelihood that this study will be successful. Our proposed work promises to provide valuable insight into the genetic causes of mTLE. It will further use that information to investigate the molecular mechanisms underlying epilepsy.